Controlled release dressing for enzymatic debridement of necrotic and non-viable tissue in a wound

ABSTRACT

A dressing for debridement of necrotic and non-viable tissue in a wound, wherein the dressing comprises an effective amount of one or more proteolytic enzymes incorporated in a degradable polymeric material. The dressing of the invention provides effective debridement of necrotic wounds over a prolonged period of time, as the enzymes may be released over time. As the enzymes are incorporated in the polymeric material, a high stability is achieved.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to a dressing such as a wound care dressing beingcapable of providing enzymatic debridement.

2. Description of the Related Art

In the treatment of chronic wounds it is often a problem that the woundcomprises necrotic or non-viable tissue and slough. The presence ofthese substances renders it difficult for the wound to heal properly aswell as it may inhibit the function of the wound dressing by preventingthat any active ingredient of the dressing may reach the wound bed.Furthermore, the slough may block/clot the surface of the dressing thuspreventing the upper layers of the dressing to function. Finally, thepresence of necrotic tissue and slough may give rise to undesiredbacterial growth. Therefore it is well known to debride such wounds e.g.by sharp, mechanical or autolytic debridement. It is also possible touse proteolytic enzymes to debride a wound and several ointments andsprays has been marketed for this purpose. Those ointments and spraystypically work within a limited period of time, and thus these productshave to be applied repeatedly, e.g. two or three times a day. Aconsequence of this would be to remove the dressing several times a dayfor application of ointment, which would be highly undesirable due tothe trauma to the skin and the patient as such, during change ofdressings. Furthermore, none of these products have the capacity tohandle the liquefied slough and degraded necrotic tissue generated bythe enzymes.

U.S. Pat. No. 4,668,228 discloses a debriding tape comprising anadhesive mass on a non-gel, non-bioerodable, biocompatible occlusive orsemi-occlusive backing, where an effective amount of a debriding enzymein dry powdered form is situated on the adhesive surface. When thepowder is brought into contact with wound exudates the entire load ofenzymes is released immediately. This dumping of enzymes may be suitablefor burns but it may not be considered optimal when dealing with chronicwounds, where a sustained release of enzyme over a prolonged periodoften is desired.

CA Patent No. 2,011,220 discloses a material with biological activitycomprising a carrier in the form of a textile, an enzyme immobilized on,and covalently bound to the carrier, 0.02-0.50% wt enzyme, 99.50-99.98%wt carrier. When the enzymes are covalently bound to the carrier theymay either stay bound during use, or the may be released when a specificenzyme, which is capable of cutting the bond, is present in the wound.If the enzymes stay bound to the carrier, the dressing will only have aneffect on the surface of the wound. The enzymes will not reach thedeeper layers and the debridement of the wound will be non-sufficient.If an enzyme capable of cutting this bond is present in the wound, theproteolytic enzyme will be released, but the patient-to-patientvariation of the amount of enzyme present is typically significant,meaning that the degree of the debridement may vary. Furthermore, inpatients suffering from dry necrosis, the enzymes in the wound may notbe able to penetrate the necrosis and no therapeutic enzyme willtherefore be released. In general, this method will release the greatestamount of debriding enzymes in areas where there is less necrosis andtherefore less need of debridement.

In U.S. Pat. No. 5,206,026 is disclosed a film for instantaneouslydelivery of enzymes to a wound. When exposed to aqueous liquid the filmrapidly dissolves, thus releasing its contents of enzymessimultaneously. No long-term release in the form of a controlled releaseis disclosed; on the contrary, a burst release is desired here.

In US patent application No. 2002/0114798 is disclosed an enzymaticwound debrider that uses a combination of a proteolytic enzyme and ananhydrous hydrophilic poloxamer carrier. The debrider is in the form ofan ointment or gel and the reference is silent with respect to anyabsorbent properties of the debrider as well as the release profile.

Thus there is still a need for a wound dressing being capable ofreleasing proteolytic enzymes over a prolonged period. This inventionhas as its primary objective the fulfillment of the above-describedneed.

SUMMARY OF THE INVENTION

One object of the invention is to provide a wound dressing for easydebridement of chronic wounds.

Another object of the invention is to provide a controlled or sustainedrelease of proteolytic enzymes to the wound.

Yet another object of the invention is to provide an easy and flexibleway of incorporation enzymes to a dressing.

Still another object of the invention is to provide an effectivedebridement of a wound without damaging the surrounding vital tissue.

A further object of the invention is to provide a less painful way ofdebriding a wound.

A still further object of the invention is to provide anenzyme-containing dressing with a good stability of the proteolyticenzyme during processing and storage of the dressing.

It has surprisingly been shown that these objects are fulfilled by thepresent invention for debridement of necrotic and non-viable tissue in awound, wherein the dressing comprises one or more proteolytic enzymesincorporated in a polymeric material that protects the proteolyticenzyme during production and storage of the dressing and furthermoreprovides a controlled release of the enzymes to the wound.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention is disclosed more in detail with reference to the drawingsin which

FIG. 1 shows a dressing according to the invention placed on a wound,

FIG. 2 shows another dressing according to the invention,

FIG. 3 shows yet another dressing according to the invention,

FIG. 4 shows a combination of the embodiments of FIGS. 2 and 3, and

FIG. 5 shows a further dressing according to the invention.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

The invention relates to a dressing for debridement of necrotic andnon-viable tissue in a wound by controlled or sustained release of oneor more proteolytic enzymes to the wound, wherein the dressing compriseswound exudates handling means in the form of an absorbent material, andan effective amount of one or more proteolytic enzymes incorporated in adegradable polymeric material, wherein the degradable polymeric materialis chosen from the group of celluloses, polyvinyl, polylactates, acrylicpolymers, polymers of glycerol and palmitostearic acid, shellac,polyurethanes, gelatine, polyethyleneglycol (PEG) and derivatives andmixtures thereof.

The dressing of the present invention comprises an effective amount ofone or more proteolytic enzymes. The enzymes may be in any suitable formand incorporated homogenously or disperse in a polymeric materialcomprising of one or more polymers. The release of the enzyme may betailored with respect to various needs. By incorporating the enzyme in adegradable polymeric material a high stability of the enzyme isprovided, both during the production of the dressing as well as duringstorage of the dressing.

Characteristics of Dressing Properties

The dressing of the present invention may be produced in varying sizesdepending on the indication, and in an adhesive version as well as anon-adhesive version. Furthermore, the dressings may be in the form ofisland dressings, with an adhesive flange surrounding an absorbentelement, or the dressing may be in the form of a paste or gel, forcavity filling. Preferably, the dressing of the invention isconformable, soft and flexible.

The dressing may comprise a backing layer, e.g. in the form of a film.This layer may preferably be water impervious but vapor permeable. Thelayer serves as a barrier against bacteria contamination from thesurroundings, and at the same time, the vapor permeability renders itpossible for the absorbed moisture (exudates) to evaporate, and thusincrease the absorbent capacity of the dressing.

The dressing of the invention comprises wound exudates handling means,thereby providing a moist-wound healing environment.

The dressing may be suitable for any wound comprising necrotic tissueincluding leg ulcers, pressure sores, diabetic foot ulcers and burns.The dressing may be used on low to highly exudating wounds. Morepreferably, the dressing exhibits good retention properties so that theabsorbed wound fluid remains in the dressing even when exposed to (some)compression. In this way the surrounding skin may be protected frommaceration.

The wound exudates handling means may comprise absorbent material suchas hydrocolloids, foam, e.g. polyurethane foam, alginates, chitosan,super absorbent material, e.g. in the form of particles or fibers, fibermaterial or it may be in the form of a hydrogel. The absorbent materialmay preferably be in the form of a layer.

The absorbent layer may have an absorption capacity of 0.9% NaCl aqueoussolution at 37° C. of at least 0.05 g/cm², more preferred at least 0.1g/cm², and most preferred at least 0.2 g/cm², even most preferred atleast 0.4 g/cm². In one embodiment of the invention the absorption is atleast 0.6 g/cm².

In one embodiment of the invention the layer comprises knitted polyestergauze impregnated with petrolatum (65-85%) and carboxymethylcellulose(5-25%). This layer may be used as a wound-contacting layer, which dueto the petrolatum, does not stick to the wound.

The dressing may also comprise combinations of the above-mentionedmaterials in order to obtain optimal wound exudate handling properties.

Characteristics of Enzymes and/or Other Active Ingredients

The dressing is designed to deliver an active component, such as anproteolytic enzyme, to the wound. In dressing constructions wheredifferent materials are combined the enzyme may be incorporated in oneor more parts of the dressing. The enzyme is incorporated in a polymericmaterial, and may be integrated in the dressing in different ways.

In one embodiment the polymeric material is in the form of a film on thewound-facing surface of the dressing. A high concentration of the enzymemay be desired on the surface of the dressing contacting the wound bedin order to obtain a more effective debridement due to a high initialrelease of the enzyme. The film may be in the form of a layer or it maybe coated on a net. The film layer may be continuous or discontinuous.

In one embodiment the enzymes and polymeric material are in the form ofparticles in the dressing. The particles can both be defined with aspecific narrow size distribution or have a very wide size distributionpattern. The particles can either be made a) as a homogenous matrixwhere enzyme and polymer are embedded or b) as a core of enzyme with acoating (shell) of polymeric material or c) as a bi-phase system whereinenzyme and polymer are separated into two phases. Enzyme will, uponwetting, release out trough channels of the polymer. As a special typeof bi-phase system there is IPN (inter penetrating network) where bothphases are continuous. A combination of the above principles may also beused. A matrix can be coated with a shell of the same or anotherpolymeric material or several small matrixes may be granulated intolarger particles. The granulation may involve the same polymers as thematrix. The coating of the particles may have any suitable thicknessdepending on the desired release time. Thus the release may becontrolled by the thickness of the coating or layer of polymer; a thicklayer or coating may degrade slower than a thin coat or layer. Spraydrying or fluid bed drying or a combination, fluid spray drying mayproduce the particles of the above principles.

The incorporation of the enzymes in the polymeric material renders themmore stable during storage and production of the dressing as they areprotected against external factors resulting in degradation, e.g. due tooxidation, degradation, denaturation, deamidation or autolysis.

The enzymes may be distributed in the absorbent material or the may bepresent on a surface of the absorbent material. If present on thesurface, the combined polymeric material and enzyme may be in the formof a layer and may be provided on the skin-facing surface of theabsorbent layer for close contact to the wound, or it may be coated onthe surface facing away from the wound in order to avoid direct contactto the wound.

Characteristics of Polymeric Material

The properties of the polymeric material may control the release ofenzyme in either a controlled or sustained release, or a burst releasefollowed by a controlled or sustained release. The release may be due toseveral mechanisms, according to the chemical nature of the polymericmaterial and the physical method of incorporation of enzyme in thepolymeric material.

When the dressing is brought into contact with moisture, e.g. in theform of wound exudate, water-molecules causes the polymer to degrade andthereby release the enzymes gradually. The mechanism of degradation ofthe polymer can be either chemical degradation, dissemble of polymericchains or swelling. The polymeric material may either absorb waterslowly, thereby releasing the enzyme slowly, or the polymeric materialmay relatively fast absorb water, and then, especially if cross-linked,create a gel on the surface of the particle, which creates a slowrelease of enzyme.

When the proteolytic enzyme is wetted, the enzymes dissolve, and diffusefrom the polymeric material and out of the dressing. The polymers may beintelligent and only release the enzyme at a specific pH optimum or if aspecific trigger compound, preferably a compound only present in chronicwounds is present.

Even a small amount of moisture may activate the release from thepolymer and thus provide a suitable release from the dressing. Thedressing may be available in different variations, according to woundexudate levels. E.g. an easily degradable polymer may provide a adequaterelease even when only low amounts of moisture is present, and a slowlydegradable polymer may be desired when used on highly exuding wound inorder to avoid release of all of the enzymes at once.

In one embodiment of the invention the wound exudates is only absorbedvertical in the dressing and thereby only facilitate release ofproteolytic enzyme where exudating wound surfaces the dressing andthereby minimizes the amount of enzyme reaching the surrounding intactskin.

A controlled release may be obtained by having a polymeric materialcomprising at least two polymers, wherein one of the polymers isdegraded faster than the other polymer. For example the controlledrelease may be achieved by coating enzymes in the form of particles witha degradable polymeric material and then incorporating the coatedparticles in a degradable polymer in the form of a film. The twodegradable polymers may be different or the same, preferably thepolymeric material selected for the film layer is degraded faster thanthe polymeric material selected for the coating. When wound exudate isabsorbed in the dressing, it causes the film to degrade and the coatedparticles of enzyme are released from the film and transported via theexudates to the wound bed, where the enzyme is released from theparticles.

The polymeric material may be selected from polymers having suitabledegradation rate when contacted with water (wound exudates). Examples ofsuch suitable polymers are in the following groups:

Celluloses:

carboxymethyl cellulose (CMC), hydroxyethyl cellulose (HEC),hydroxypropyl cellulose (HPC), ethyl cellulose (EC), hydroxypropylmethylcellulose (HPMC), polysaccharides, cellulose acetate phthalate (CAP),microcrystalline cellulose (MCC), cellulose acetate butyrate (CAB),cellulose acetate trimellitate (CAT), hydroxypropyl methylcellulosephthalate (HPMCP)

Polyvinyls:

polyvinylpyrrolidone (PVP), copolymer of vinylpyrrolidone, polyvinylacetate phthalate (PVAP), polyvinyl alcohol (PVA) and vinylacetate

Acrylic Copolymers:

copolymers of methacrylic acid, methacrylic alkylester, cross-linkedpolyacrylic acid,

Poylactates

DL-PLG poly(DL-lactide-co-glycolide), DL-PLA poly(DL-lactide), L-PLApoly(L-lactide), PGA poly(glycolide) or PCL poly(e-caprolactone).

Others:

polymers of glycerol and palmitostearic acid, Shellac, polyurethanes,gelatine, polyethyleneglycol (PEG)

The polymeric material can be used with a range of different molecularweights, grades, degree of substitution and different degrees ofcross-linking, and either native in the raw material or induced duringproduction processes.

The polymeric material may be in the form of a film or it may be in theform of a coating of the enzymes. The polymeric material may beincorporated in a layer, which is in direct contact with the wound.

Characteristics of Enzyme

The enzyme(s) suitable for the invention may be proteolytic enzymescapable of degrading devitalized tissue, eschar and slough. Theenzyme(s) may be proteolytic enzymes capable of degrading proteins, suchas fibrin, denatured collagen and elastin. The enzymes should bedebriding when contacted with necrotic tissue but have minimal impact onvital tissue.

The enzyme may preferably be chosen from the group of bromelain,collagenase, fibrinolysin, deoxyribonuclease, krillase, papain,streptokinase, streptodornase, sutilains, subtilisin, trypsin andvibriolysin. The enzyme may be of natural origin or produced by GMO andmay be with a very high purity (e.g. 99.9%) or constitute a mixture ofenzymes or other entities natural occurring in the origin of the enzymeraw material.

A Preferred Enzyme is Papain.

In a preferred embodiment the enzyme is a refined papain-preparationfrom the papaya fruit and may thereby contain other active enzymes thanthe enzyme papain.

The effective amount of enzyme may differ depending upon the desiredapplication as well as the chosen enzymes. In general the amount ofenzyme is determined in order to obtain effective debriding propertiesof the dressing, e.g. so that most wounds are debrided within 14 days oftreatment using this/these dressing(s). Preferably, the dressing of thepresent invention exhibits enzyme activity and debriding properties thatbegin a few hours after the dressing has been applied and lasts for upto several days. The dressing of the present invention may releaseenzymes/exhibit enzyme activity over a period of at least 12 hours, morepreferred 24 hours, even more preferred 48 hours and most preferred 96hours. In one embodiment of the invention the dressing exhibits enzymeactivity for more than 7 days, more preferred more than 6 days and evenmore preferred more than 5 days.

For papain, suitable amounts of enzymes in the dressing of the presentinvention are up to 1×10⁷ USP units per cm² preferably 1×10⁴ to 2×10⁶and more preferably 2×10⁴ to 1×10⁶. For other enzymes lower or higheramounts may be appropriate to be equivalent to the described debridingeffect of papain.

The enzyme may be activated by different means e.g. when brought incontact with wound exudate. It is preferred that the enzyme activitylasts during the recommended wear time of the dressing, depending on theamount of exudate.

It is preferred that the enzyme activity stretches over a prolongedperiod of time, as dressing changes often are traumatic for both thewound and the patient. The release or the enzyme activity may becontrolled in such a way that a determined amount of enzyme (activity)is released per time unit, this may be the same amount over time, or itmay e.g. be a boost shortly after the dressing is applied, followed by alower release over the next days.

Other Active Agents

Other suitable active agents may be incorporated into the dressing ofthe invention, such as charcoal to remove odor or hormones thatstimulates healing. Other suitable enzymes for debriding, surfactants,such as urea for softening necrotic tissue and expose dead proteinaceousmaterial and stabilizers of the proteolytic enzyme such as cysteine andEDTA may also be present.

In order to control bacteria in the wound bed and to avoid bacteriagrowth in the dressing during wear time, the dressing may furthercomprise an antiseptic or antibacterial agent such as a silver compound,hypochlorite, chlorhexidine or other antibacterial compounds known inthe art.

The debridement process as well as dressing changes may give rise topain for the patient, and thus it may be preferred to incorporate a apain-relieving agent such as an analgesic or an anesthetic compound inthe dressing of the present invention.

The dressing of the present invention may further comprise debridingcompositions other than enzymes, which may have additive or synergisticdebriding effect. An example of such compound may be urea.

The dressing of the invention may also be suitable for use for treatmentof skin diseases, such as psoriasis or other forms of skin treatment.

Description of the Preferred Embodiments

FIG. 1 shows a dressing according to the invention placed on a wound inneed of debridement. The dressing comprises a degradable film (orimpregnated mesh net) with enzymes incorporated therein (1), anabsorbent material (2) and a backing film (3). The dressing is placedupon necrotic tissue (4), which in this case covers the entire wound bed(5).

FIG. 2 shows another dressing according to the invention comprisingenzymes in the form of particles (12) coated with a degradable polymer(14) incorporated in an absorbent material (11). The dressing furthercomprises a backing film (13).

FIG. 3 shows a dressing according to the invention comprising enzymes inthe form of particles (22) coated with a degradable polymer (25)incorporated in a layer of a degradable polymer film (21). The layer mayserve as a wound-contacting layer. The dressing further comprises anabsorbent material (23) and a backing film (24).

FIG. 4 shows a combination of FIGS. 2 and 3, wherein the enzymes in theform of polymer-coated particles (31) are incorporated in both theabsorbent layer (32) and the degradable wound contacting film layer(33). The dressing further comprises a backing layer (34).

FIG. 5 shows a dressing according to the invention comprising anabsorbent material (41), a backing film (44) and a degradable polymericmaterial (43) placed in vertical canals or cavities (45). The enzymesare in the form of particles (42) incorporated in the degradable polymermaterial (43).

EXAMPLES Example 1 Degradable Film on Dressing

A dressing of the kind shown in FIG. 1 was prepared by mixing 8 gHypol2060 (Dow Chemical Company), 12 g of Hypol 2002 and 20 g of waterwith 1% w/w Pluronic 62 (BASF AG). The materials were mixed together forapproximately 15 seconds. The liquid was poured into a mould and allowedto react for 10 minutes. The resulting foam sheet was dried in an ovenat 70° C. for 30 minutes and had a thickness of 3 mm. A polyurethane(PU) backing film was laminated on the top of the foam, thus sealing thedressing from outside. The water permeability of the backing film was500 g pr m² pr hour. The foam was supporting the backing film physicallyand comprised the exudates absorbing properties of the dressing.

A polymer film was casted on a silicone release liner 1022 (Scotch Pak,3M Medica) using a polymer solution of PVP K90 (5% w/w), K25 (24%),Permulen (5% w/w), Polyurethane, DC-01-1628 (24% w/w), PEG 300 (37% w/w)and papain (5% w/w). When the polymer film was almost dry, it wasapplied to the foam using a light pressure. A refined release-assay wasused, using saline phosphate buffer, pH=7.4. as release medium, whereinthe dressing was wetted in approximately the same rate as when adressing is applied on an average wound and absorbs wound exudate. Itwas observed that substantially all of the incorporated enzyme wasreleased within 3 hours.

Example 2A Enzyme Coated in HPC and Embedded in a Polyurethane Foam

A dressing of the kind shown in FIG. 2 was prepared using 500 g of anaqueous solution containing papain (2% w/w) mixed with 10 g ofhydroxypropylcellulose (HPC) and spray dried on a Niro FSD 6.5 spraydrier, resulting in particles comprising of a homogenous blend ofpolymer and enzyme in a ratio of 1:1. The mean particles size was 100μm. A polyurethane foam was prepared as described in Example 1, howeverthe particles were added during mixing of the foam components. In therefined release-assay substantially all the enzyme was released with nosignificant loss of activity compared to control. 95% of the enzyme wasreleased within 24 hours in a constant release pattern.

Example 2B Enzyme Coated in HPC and Embedded in a Polyurethane Foam

As in 2A, but instead 20 gr. of HPC was used, thus obtaining a ratio of2:1 between the polymer and the enzyme. Approximately 95% of the enzymewas released within 36 hours in a constant release pattern.

Example 2C Enzyme Coated in HPC/Eudragit and Embedded in a PolyurethaneFoam

As in 2A but instead of HPC a mixture of HPC and Eudragit 30RL was usedin the ratio of 1:1. Approximately 95% of enzyme was released within 48hours with constant release pattern.

Example 2D Enzyme Coated in HPMC and Embedded in a Polyurethane Foam

As in 2A but HPC was replaced with hydroxypropylmethylcellulose (HPMC).Approximately 95% of enzyme was released within 72 hours with constantrelease pattern.

Example 2E Enzyme Coated in NaCMC and Embedded in a Polyurethane Foam

As in 2B but HPC was replaced with natriumcarboxymethylcellulose(NaCMC). Approximately 95% of enzyme was released within 96 hours withconstant release pattern.

Example 2F Enzyme Coated in PVP and Embedded in a Polyurethane Foam

A 10% w/w solution of enzyme was spray dried. In a fluid bed theparticles was coated with PVP. Approximately 95% of enzyme was releasedwithin 24 hours with constant release pattern.

Example 2G Enzyme Directly Embedded in a Polyurethane Foam

As a comparative study, the enzyme was directly embedded in a foam byadding 10 g of an aqueous solution containing papain (10% w/w) with 8 gHypol2060 (Dow Chemical Company), 12 g of Hypol2002 and 10 g of waterwith 2 part w/w Pluronic 62 (BASF). A foam sheet was prepared as inExample 1. In the release-assay approximately 10% of the incorporatedenzyme were released within 6 hours, while the rest of enzyme isretained in the dressing. A considerable loss of activity was observed.

Example 3A Enzyme Coated in Particles and Added to a Film

A dressing of the kind shown in FIG. 3 was prepared. 100 g of an aqueoussolution containing the enzyme Papain (10% w/w), cysteine (0.1% w/w) andEDTA (0.1% w/w) was added to 10 g of a DL-PGL-polymer (50:50) polymermixture and spray dried into micro/particles with a particle size in therange of 50-200 μm. 20 g of the coated particles and 10 g of urea werethen quickly extruded into a gel of hydroxypropylcellulose (HPC, 30%w/w). With the particles in suspension, the film was directly castedinto a film on a silicone release liner and dried for 5 min at 45° C.under airflow. The coat weight of the resulting film was 150 gsm. Thefilm was attached to a 3 mm thick polyurethane foam sheet, prepared asdescribed in Example 1.

Example 3B Gauze Impregnated with Particles

An enzyme blend containing 10 g Papain, 100 mg cysteine and 100 mg EDTAwas mixed into a 100 g polymer solution consisting of ethanol (40% w/w),water (40% w/w) and DL-PGL-polymers (20% w/w). Another mixturecomprising 10 g of urea mixed into an equivalent amount of the polymersolution was prepared. The two mixtures were then shortly blended andcotton gauze was impregnated with the polymer solution resulting in acoat weight of 100 gsm. The gauze was placed as a wound contact layer ina dressing with a 3 mm water absorbing layer containing super absorbentfibers as the dressing of EP Patent Application No. 1,303,239. In therelease-assay wound exudate was absorbed by the dressing through theimpregnated gauze and upon wetting of the gauze the impregnation wasslowly dissolved and enzyme was gradually released. After a short lagtime the release followed a zero-order profile with release of 0.3 mgpr. cm² pr. hour in 72 hours. After 72 hours the amount of enzymedepleted.

Example 3C Dressing with Combines Burst Release and Controlled Release

A burst release film was prepared by mixing papain (14% w/w), PVP K90,Mw 1,300,000 (9% w/w), PVP K25, Mw 34,000 (12% w/w), PEG400 (21% w/w)and PEG4000 (44% w/w). The mix was melted at 65° C. in a double-screwextruder and with a nozzle coated in a homogenous layer onto a foamsheet prepared as in Example 2A. The thickness of the layer was measuredto 88 μm and the papain content to 0.51 mg/cm². In the release assay itwas shown that substantially all of the enzyme of the burst releaselayer was released within 30 min, while 95% of the enzyme of the foamlayer was released within 24 hours in a constant release pattern.

Example 4 Enzyme in a Film Attached to a Polyurethane Foam Sheet, withEnzyme (in Particles)

A dressing of the kind shown in FIG. 4 was prepared. A film was preparedas in Example 1, however instead of attaching the film to a non-activefoam, the foam in Example 2B was used. In the release model it was shownthat 30% of the total enzyme amount was released within 3 hours, whereafter the release rate continued with a lower rate. All enzyme wasreleased at 30 hours.

Example 5 Example 5—Foam with Vertical Canals Releasing Enzyme

A polyurethane foam was prepared as in Example 1. Holes of 1 mm indiameter were punched out in the foam in a grid, with 1 hole pr. cm². A10% papain solution was spray dried and the powder was mixed with PEG600 (ratio 50:50) and filled into a syringe. A needle was attached andthe holes were filled up and the dressing was allowed to dry. In therelease model a zero-order profile was observed with depletion at 72hours.

Example 6 Enzyme at Top Film

A powder of enzyme was produced as in Example 2A and was poured directlyon the backing film. A solution for a polyurethane foam was prepared asin Example 1 and was casted directly on the backing film. The resultingfoam sheet was dried in an oven at 70° C. for 30 minutes and had athickness of 3 mm. The foam was supporting the backing film physicallyand comprised the exudates absorbing properties of the dressing. In arelease assay substantially all the enzyme was released with nosignificant loss of activity compared to control. After a lag time of 2hours 95% was released within 48 hours in a constant release pattern.

1. A dressing for debridement of necrotic and non-viable tissue in awound by controlled or sustained release of one or more proteolyticenzymes to the wound, said dressing comprising, 1) an absorbent materiallayer; 2) an amount of particles effective for debridement of necroticand non-viable tissue, said particles containing one or moreproteolytic, debridement enzymes, said enzyme particles coated with afirst degradable polymeric material, the first degradable polymericmaterial being selected from the group consisting of celluloses,polyvinyl, acrylic polymers, polylactates, polymers of glycerol andpalmitostearic acid, shellac, polyurethanes, gelatin, polyethyleneglycol (PEG) and derivatives and mixtures thereof; 3) a layer of asecond degradable polymeric material; wherein the second degradablepolymer is more quickly degraded than the first degradable polymer;wherein a first side of the absorbent material layer is in contact withthe enzyme particles coated with the first degradable polymer; whereinthe layer of the second degradable polymer is a film which covers theabsorbent material and the enzyme particles; and wherein said dressinghas a backing layer covering a second side of the absorbent materiallayer.
 2. The dressing according to claim 1, wherein the enzymeparticles are distributed in the absorbent material.
 3. The dressingaccording to claim 1, wherein the enzyme particles are present on asurface of the absorbent material.
 4. The dressing according to claim 1,wherein the first polymeric material coating the enzyme particles is indirect contact with the wound.
 5. The dressing according to claim 1,wherein the enzyme is papain.
 6. The dressing according to claim 1,wherein the dressing further comprises a pain-relieving agent.
 7. Thedressing according to claim 1, wherein the dressing further comprises anantibacterial agent.
 8. The dressing according to claim 1, wherein thedressing further comprises urea.
 9. The dressing according to claim 2,wherein the absorbent material comprises polyurethane foam.
 10. Thedressing according to claim 1, wherein said enzyme particles beingincorporated into the layer of degradable polymeric film on a woundfacing surface of the dressing.
 11. The dressing of claim 10, whereinthe degradable polymeric film incorporating the enzyme particlesdegrades faster than the degradable polymer coating on the particles.12. The dressing of claim 10, wherein the degradable polymeric filmincorporating the enzyme particles is comprised of a polymer solution ofpolyvinylpyrrolidone, 1-Vinyl-2-pyrrolidinone homopolymer (5% W/W),1-Ethenyl-2-pyrrolidinone homopolymer (24% W/W), acrylate/C10-30 alkylacrylate crosspolymer (5% W/W), Polyurethane (24% W/W) and PEG 300 (37%W/W).
 13. The dressing according to claim 1, wherein said enzymeparticles being incorporated into said absorbent material of thedressing.
 14. The dressing of claim 13, wherein said absorbent materialcomprises polyurethane foam.
 15. The dressing of claim 14, also havingenzyme particles incorporated into the layer of degradable polymericfilm on the wound facing surface of the dressing.
 16. The dressingaccording to claim 1, wherein said enzyme particles are incorporatedwithin vertical canals or cavities extending from openings on a woundfacing side of said absorbent material.